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Methods for producing and using in vivo pseudotyped retroviruses using envelope glycoproteins from lymphocytic choriomeningitis virus (LCMV)

a technology of lymphocytic choriomeningitis virus and envelope glycoprotein, which is applied in the direction of viruses, peptides, vectors, etc., can solve the problem that the application of viral vectors in vivo is often limited

Active Publication Date: 2005-06-09
IOWA RES FOUND UNIV OF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides a method for delivering a remedial gene to a target cell in the nervous system, such as an airway epithelial cell, a central nervous system cell, or a hepatocyte cell, by using a pseudotyped retrovirus virion containing an LCMV envelope glycoprotein. The envelope glycoprotein can have a phenylalanine at residue 260 and / or a phenylalanine at residue 153, and the virion can also contain a variant envelope glycoprotein with a phenylalanine at residue 260 and / or a phenylalanine at residue 153. The invention also provides a method for producing infectious particles containing the remedial gene, as well as a packaging cell that stably expresses the pseudotyping LCMV envelope glycoprotein."

Problems solved by technology

In addition, in vivo application of viral vectors is often limited by host immune responses against viral structural proteins and / or transduced gene products.

Method used

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  • Methods for producing and using in vivo pseudotyped retroviruses using envelope glycoproteins from lymphocytic choriomeningitis virus (LCMV)
  • Methods for producing and using in vivo pseudotyped retroviruses using envelope glycoproteins from lymphocytic choriomeningitis virus (LCMV)
  • Methods for producing and using in vivo pseudotyped retroviruses using envelope glycoproteins from lymphocytic choriomeningitis virus (LCMV)

Examples

Experimental program
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Effect test

example 1

LCMV Pseudotyped FIV Targets the Apical Surface of Airway Epithelia for Entry

[0188] The inventors evaluated the ability of LCMV glycoproteins (GPs) to pseudotype the FIV vector. LCMV-GP is initially expressed as a precursor polypeptide, GP-C, which is post-translationally processed by a cellular protease into GP1 and GP2. GP1 meditates binding to the cellular receptor for LCMV, and GP2 contains the fusion peptide and the transmembrane region [Buchmeier et al., supra]. Recently Beyer and colleagues reported successful pseudotyping of HIV-based lentivirus vectors with glycoproteins from the LCMV WE54 strain [Beyer et al., J. Virol. 76:1488-1495 (2002)]. In contrast to amphotropic-MLV vector particles, LCMV pseudotypes could be efficiently concentrated by ultracentrifugation without loss of vector titer. The inventors obtained the LCMV strain WE54 GP from Dr. Beyer and evaluated its efficiency in pseudotyping FIV. Titers for the FIV pseudotyped with LCMV WE54 were ˜5×108 TU / ml, very s...

example 2

Receptors for LCMV

[0190] Alpha-dystroglycan (alpha-DG) was identified as a high affinity receptor for several arenaviruses including some strains of LCMV, Lassa virus, Oliveros virus, and Latino virus [Cao et al., Science, 282:2079-2081 (1998)]. Dystroglycan is a dystrophin-associated glycoprotein that connects the cytoskeleton with the extracellular matrix and is widely expressed in most tissues, including the lung [Henry and Campbell, Cell, 95:859-870 (1998); White et al., Am. J. Respir. Cell. Mol. Biol. 24:179-86 (2001)]. Dystroglycan is post-translationally cleaved into a highly glycosylated peripheral membrane protein alpha-DG, which is noncovalently associated with the membrane-spanning protein beta-dystroglycan [Henry and Campbell, Curr. Opin. Cell Biol., 11:602-607 (1999)]. Beta-dystroglycan is linked to the cytoskeleton. It is important to note that studies with wildtype LCMV WE54 strain demonstrate high affinity binding to alpha-DG (Spiropoulou et al., supra). However, so...

example 3

Gene Transfer to Mouse Liver Using FIV Pseudotyped with LCMV Envelope

[0192] Gene transfer to the liver has potential clinical applications for many diseases. The inventors evaluated the liver transduction properties of the FIV pseudotyped with LCMV-L260F. For systemic vector delivery to the liver, C57BL / 6 mice received the LCMV pseudotyped FIV vector intravenously via the tail vein using methods as previously described [Stein et al., Mol. Ther., 3:850-856 (2001); Kang et al., J. Virol., 76:9378-9388 (2002)]. Three weeks later the animals were killed and the liver tissues examined for beta-galactosidase expression. Widespread expression was observed throughout the liver samples. This tropism for liver is useful for the production of secreted proteins or treatment of disorders primarily involving liver parenchyma, such as the mucopolysaccharidoses.

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Abstract

The present invention provides novel pseudotyped retroviral vectors that can transduce human and other cells. Vectors are provided that are packaged efficiently in packaging cells and cell lines to generate high titer recombinant virus stocks expressing novel envelope glycoproteins. The present invention further relates to compositions for gene therapy.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of U.S. Ser. No. 10 / 718,262, filed Nov. 20, 2003.U.S. GOVERNMENT RIGHTS [0002] Portions of the present invention were made with support of the United States Government via a grant from the National Institutes of Health under grant numbers PPG HL-51670, DK54759, and NS34568. The U.S. Government therefore may have certain rights in the invention.FIELD OF THE INVENTION [0003] The present invention relates to improved pseudotyped retrovirus-derived vectors useful for the expression of genes in eukaryotic cells. BACKGROUND OF THE INVENTION [0004] Viral vectors transduce genes into target cells with high efficiencies owing to specific virus envelope-host cell receptor interaction and viral mechanisms for gene expression. Consequently, viral vectors have been used as vehicles for the transfer of genes into many different cell types. The ability to introduce and express a foreign gene in a cell is usef...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00C07K14/08C12N5/10C12N15/867
CPCA61K48/00C07K14/005C12N15/86C12N2810/6072C12N2740/15045C12N2760/10022C12N2740/15043
Inventor MCCRAY, PAUL B. JR.DAVIDSON, BEVERLY L.STEIN, COLLEEN
Owner IOWA RES FOUND UNIV OF
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